Sequential cleavage of APP by - and -secretase yields A peptides that are pathogenic in Alzheimer's Disease (AD), along with AID/AICD, which mediates APP signaling. Some APP and -secretase mutations alter the rate of A production and cause autosomal dominant familial AD (FAD). Given the role of APP processing in AD and APP-mediated functions, modulators of APP cleavage such as BRI2 are biologically relevant and of therapeutic interest. Of note, BRI2 mutations cause autosomal dominant Familial British (FBD) and Familial Danish (FDD) Dementia two AD-like diseases. We have further studied the significance of the BRI2-APP interaction and found that: 1) BRI2 inhibits APP processing and A generation; 2) BRI2 mutants that cause FBD and FDD are poor inhibitors of APP processing. Thus, our WORKING HYPOTHESIS is that: A) BRI2 is a competitive inhibitor of APP cleavage by secretases; B) BRI2 regulates AD pathogenesis; C) FBD and FDD BRI2 mutants exacerbate the progression of AD, and dis- regulation of APP processing may participate in FDD and FBD pathogenesis. This grant has three Aims in which we propose to test these hypotheses.